An Expeditious and Efficient Procedure for the Synthesis of

An Expeditious and Efficient Procedure for the Synthesis of Unsaturated Acyclonucleosides of Z Configuration Related to D4T Fernando Bravo, Antonio Viso, and Sergio Castillo´n* Departament de Quı´mica Analı´tica i Quı´mica Orga` nica, Facultat de Quı´mica, Universitat Rovira i Virgili, Pza. Imperial Tarraco 1, 43005 Tarragona, Spain [email protected] Received September 25, 2001

Abstract: Enantiopure 2,5-dihydrofuran derivatives were prepared from (S)-glycidol through a new reaction sequence involving epoxide opening with a vinylcuprate, seleniuminduced cyclization to give exclusively the 5-endo product, and regioselective selenoxide elimination. Unsaturated acyclonucleosides of Z configuration were obtained in a straightforward manner by treating 2,5-dihydrofuran with iodotrimethylsilane in the presence of silylated purinic or pyrimidinic bases. This synthetic process involves opening of the dihydrofuran ring by trimethylsilyl iodide and substitution of iodine by the nucleic base in a single reaction step.

Unsaturated nucleosides such as d4T1 (1) and neplanocin A2 (2) are strong inhibitors of HIV reverse transcriptase and S-adenosylhomocysteine-hydrolase. Prompted by these findings and by the fact that several acyclonucleosides3 such as acyclovir,4 (3) gancyclovir5 (4), and pencyclovir6 (5) are currently used in the treatment of several viral diseases, different unsaturated acyclonucleosides were prepared and tested as antiviral and antitumor agents. Nucleosides 67 and 7,8,9 conceptually derived from 1 by removing the furanose oxygen or breaking the O-C1 bond, respectively, and 8 (R ) H)8-10 showed only weak antiviral activity. However, the pres(1) Barrish, J. C.; Zahler, R. Antiviral Agents. In Ann. Rep. Med. Chem. 1993, 28, 131-140. (2) Marquez, V. E.; Lim, M. I. Med. Res. Rev. 1986, 6, 1-40. (3) (a) El Ashry, E. S. H.; El Kilany, Y. Adv. Heterocycl. Chem. 1997, 67, 391. (b) El Ashry, E. S. H.; El Kilany, Y. Adv. Heterocycl. Chem. 1997, 68, 1. (c) El Ashry, E. S. H.; El Kilany, Y. Adv. Heterocycl. Chem. 1997, 69, 129. (4) (a) Elion, G. B.; Furman, P. A.; Fyfe, J. A.; de Miranda, P.; Beauchamp, L.; Schaeffer, H. Proc. Natl. Acad. Sci. U.S.A. 1977, 74, 5716-5720. (b) Gao, H.; Mitra, A. K. Synthesis 2000, 329-351. (5) (a) Field, E. K.; Davies, M. E.; DeWitt, C.; Perry, H. C.; Liou, R.; Germershausen, J.; Karkas, J. D.; Ashton, W. T.; Johnston, D. B. R.; Tolma, R. L. Proc. Natl. Acad. Sci. U.S.A. 1983, 80, 4139-4143. (b) Martin, J. C.; Dvorak, C. A.; Smee, D. F.; Matthews, T. R.; Verheyden, J. P. H. J. Med. Chem. 1983, 26, 759-761. (c) Smee, D. F.; Martin, J. C.; Verheyden, J. P. H.; Matthews, T. R. Antimicrob. Agents Chemother. 1983, 23, 676-682 (6) Harnden, M. R.; Jarvest, R. L.; Bacon, T. H.; Boyd, M. R. J. Med. Chem. 1987, 30, 1636-1642. (7) (a) Shirokova, E. A.; Tarussova, N. B.; Shipitsin, A. V.; Semizarov, D. G.; Krayevsky, A. A. J. Med. Chem. 1994, 37, 3739-3748. (b) Shirokova, E. A.; Tarussova, N. B.; Shipitsin, A. V.; Semizarov, D. G.; Hieber, A.; Krayevsky, A. A. Nucleosides Nucleotides 1995, 14, 749752. (8) Borcherding, D. R.; Narayanan, S.; Hasobe, M.; McKee, J. G.; Keller, B. T.; Borchardt, R. T. J. Med. Chem. 1988, 31, 1729-1738. (9) Phadtare, S.; Kessel, D.; Corbett, T. H.; Renis, H. E.; Cout, B. A.; Zemlicka, J. J. Med. Chem. 1991, 34, 421-429.

FIGURE 1.

ence of a phosphonate7,11 group (8, R ) CH2P(O)(OH)2, base ) adenine) or phosphoroalaninate (8, R ) [CH3O2CCH(CH3)NH]P(O)(OH)2, base ) adenine)12 in place of the free OH significantly increases the antiviral activity. Compound 8 (R ) CH2P(O)(OH)2, base ) thymine) has also been shown to be an inhibitor of the thymidine phosphorylase.13 Unsaturated acyclonucleosides of Z configuration are currently prepared in several ways: (a) by nucleophilic substitution of appropriately protected propargyl derivatives followed by reduction,7 (b) by selective protection of cis-2-butene-1,4-diols, followed by halogenation and substitution,10,12 (c) from cis-1,4-dichloro2-butene,11 or (d) from chiral glyceraldehyde with the cis selective Horner-Emmons reaction.8 In this Note we describe an expeditious, highly efficient and stereoselective procedure for synthesizing unsaturated acyclonucleosides of Z configuration from 2,5-dihydrofuran, as well as a direct method to prepare chiral enantiopure 2,5-dihydrofuran derivatives. There are only a few examples of 2,5-dihydrofuran opening under acidic conditions. They involve the use of acetic-toluenesulfonic mixed anhydride,14 acetyl chloride and CoCl215 or Mo(CO)6 as catalyst,16 acetyl bromide,17 or Et2NSiMe3/MeI as an equivalent of iodotrimethylsilane.18 Iodotrimethylsilane (Me3SiI) is a particularly (10) Ashton, W. T.; Meurer, L. C.; Cantone, C. L.; Field, A. K.; Hannah, J.; Karkas, J. D.; Liou, R.; Patel, G. F.; Perry, H. C.; Wagner, A. F.; Walton, E.; Tolman, R. L. J. Med. Chem. 1988, 31, 2304-2305. (11) (a) De Clercq, E. J. Med. Microb. 1999, 47, 1-3. (b) De Clercq, E.; Intervirology 1998, 40, 295-303. (c) Bzowska, A.; Kulikowska, E.; Shugar, D. Pharmacol. Ther. 2000, 88, 349-425. (12) (a) Winter, H.; Maeda, Y.; Uchida, H.; Mitsuya, H.; Zemlicka, J. J. Med. Chem. 1997, 40, 2191-2195. (b) Winter, H.; Maeda, Y.; Mitsuya, H.; Zemlicka, J. Nucleosides Nucleotides 1997, 16, 13411345. (13) Esteban-Gamboa, A.; Balzarini, J.; Esnouf, R.; De Clercq, E.; Camarasa, M. J.; Pe´rez-Pe´rez, M. J. J. Med. Chem. 2000, 43, 971983. (14) (a) Karger, M. H.; Mazur, Y. J. Org. Chem. 1971, 36, 532-540. (b) Corey, E. J.; Kirst, H. A. J. Am. Chem. Soc. 1972, 94, 667-668. (15) Iqbal, J.; Srivastana, R. R. Tetrahedron 1991, 47, 3155-3170. (16) Alper, H.; Huang, C. C. J. Org. Chem. 1973, 38, 64-71. (17) (a) Steinig, A. G.; de Meijere, A. Eur. J. Org. Chem. 1999, 13331344. (b) Hrebabecky, H.; Holy, A. Collect. Czech. Chem. Commun. 1999, 64, 1485-1496. (18) Oshita, J.; Iwata, A.; Kanetami, F.; Kunai, A. J. Org. Chem. 1999, 64, 8024-8026. 10.1021/jo010948r CCC: $25.00 © 2003 American Chemical Society

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Published on Web 12/28/2002

SCHEME 1

efficient reagent for ether cleavage.19 It has also been used as a promotor in glycosylation reactions leading to oligosaccharides20 and nucleosides,21 as well as in the synthesis of acyclonucleosides from acyclic donors.22 We expected that iodotrimethylsilane would open the 2,5dihydrofuran ring to give an iododerivative that would convert to an acyclonucleoside in the presence of a purine or pyrimidine base. Initially, we treated commercially available dihydrofuran 9 with bis(trimethylsilyl)thymine in the presence of Me3SiI in refluxing chloroform, and we observed that compound 11 was quickly formed (Scheme 1). Although the Z isomer predominated, some isomerization to the E-alkene occurred with increasing the reaction time (ratio Z/E ) 23:1 at 10 min and 5:1 at 30 min).9,23 The E isomer was produced in a Z/E ) 20 ratio when the reaction was performed at room temperature, but the reaction was much slower. Although previous reports stated that refluxing 2,5-dihydrofuran with Et2NSiMe3/MeI gave almost exclusively the E isomer,18 in our case the Z isomer was always the major product, probably because the initially formed intermediate 10 is transformed into the nucleoside prior to isomerization. The 2,5-dihydrofuran was recovered unchanged when TMSI was replaced with TMSOTf, suggesting that intermediate 10 is initially formed. In fact, the allylic iodide 10 was detected when the reaction was conducted in the absence of the nucleic base. Although the Z/E mixture of 11 was inseparable, the acyl derivatives 12 and 13 allowed the isolation of the Z isomer in pure form. (19) (a) Kamal, A.; Laxman, E.; Rao, N. V. Tetrahedron Lett. 1999, 40, 371-372. (b) Olah, G. A.; Prakash, G. K.; Krishnamurti, R. Adv. Silicon Chem. 1991, 1, 1-64. (c) Jung, M. E.; Lyster, M. A. Org. Synth. 1980, 59, 35-41. (d) Ho, T.-L.; Olah, G. A Proc. Natl. Acad. Sci. U.S.A. 1978, 75, 4-6. (e) Ho, T.-L.; Olah, G. A. Angew. Chem., Int. Ed. Engl. 1976, 15, 774-75. (20) (a) Gervay, J.; Hadd, M. J. J. Org. Chem. 1997, 62, 6061-6067. (b) Uchiyama, T.; Hindsgaul, O. Synlett 1996, 499-500. (21) Ohsawa, K.; Shiozawa, T.; Achiwa, K.; Terao, Y. Chem. Pharm. Bull. 1993, 41, 1906-1909. (22) Ubasawa, M.; Takashima, H.; Sekiya, K. Nucleosides Nucleotides 1998, 17, 2241-2247. (23) (a) Hua, M.; Korkowski, P. M.; Vince, R. J. Med. Chem. 1987, 30, 198-200. (b) Phadtare, S.; Zemlicka, J. J. Med. Chem. 1987, 30, 437-440.

SCHEME 2

Similarly, compound 14 was obtained in 60% yield starting from N6-benzoyl-N,69-bis(trimethylsilyl)adenine.24 The Z isomer was obtained by crystallization. Deprotection of amine 14 by reaction with PrNH2/MeOH provided the acyclonucleoside 15. We next applied this procedure to the synthesis of chiral acyclonucleosides 20 and 21 (Scheme 2). We have recently reported that the mode of cyclization of 4-pentene-1,2,3-triols can be governed by the electrophile. Thus, iodo electrophiles give the 5-exo cyclization involving the primary hydroxyl, while selenium electrophiles give the 5-endo cyclization by involving the secondary hydroxyl.25 It is also known that selenoxide is preferentially eliminated to give C-C double bonds instead of enolethers.26In this context, glycidol 16 was treated with a vinylcuprate to obtain the alkenediol 17 in excellent yield.27 Compound 17 was then reacted with phenylselenenylphthalimide (PhthSePh) in the presence of catalytic camphorsulfonic acid (CSA) to obtain the tetrahydrofuran 18, resulting from 5-endo cyclization, as a 25: 75 mixture of diastereomers in 82%.25 The mixture of selenotetrahydrofurans 18 was oxidized by treatment with hydrogen peroxide to give exclusively the 2,5(24) Lichtenthaler, F. W.; Voss, P.; Heerd, A. Tetrahedron Lett. 1974, 24, 2141-2144. (25) Bravo, F.; Castillo´n, S. Eur. J. Org. Chem. 2001, 507-516. (26) For similar regioselective eliminations of selenoxides, see: (a) Sharpless, K. B.; Young, M. W.; Lauer, R. F. Tetrahedron Lett. 1973, 1979-1982. (b) Nicolaou, K. C.; Barnette, W. E. J. Chem. Soc., Chem. Commun. 1977, 331-332. (c) Nicolaou, K. C.; Lysenko, Z. Tetrahedron Lett. 1977, 18, 1257-1260. (d) Nicolaou, K. C.; Magolda, R. L.; Sipio, W. J.; Barnette, W. E.; Lysenko, Z.; Jouille, M. M. J. Am. Chem. Soc. 1980, 102, 3784-3793. (e) Paquette, L. A.; Ezquerra, J.; He, W. J. Org. Chem. 1995, 60, 1435-1447. (27) Dı´az, Y.; Bravo, F.; Castillo´n, S. J. Org. Chem. 1999, 64, 65086511.

J. Org. Chem, Vol. 68, No. 3, 2003 1173

dihydrofuran 19.26 The reaction of dihydrofuran 19 with bis(trimethylsilyl)thymine in the presence of Me3SiI gave 20 in 92% yield, although the reaction rate was much slower. Treatment of compound 20 with Bu4NF provided the acyclonucleoside 21 related to d4T (1) in 97% yield. The adenine derivative 22 was similarly produced in good yield, by treating 19 with N6-benzoyl-N,69-bis(trimethylsilyl)adenine. No traces of the E isomer were observed in either case. In conclusion, a new methodology has been developed for the stereo- and regioselective synthesis of acyclonucleosides analogous to the antiviral dideoxydidehydronucleosides. The Z-selectivity of this process involving the intermediacy of reactive allylic iodides of Z-configuration is particularly noteworthy. Experimental Section General Procedures. Melting points are uncorrected. Optical rotations were measured at 25 °C in 10-cm cells. 1H NMR and 13C NMR spectra were recorded on 300 or 400 MHz (300, 75.4 and 400, 100.5 MHz, respectively) Varian equipment, with CDCl3 as solvent, unless otherwise specified. Coupling constants are given in hertz (Hz). Elemental analyses were determined at the Servei de Recursos Cientı´fics (Universitat Rovira i Virgili). Flash column chromatography was performed using silica gel 60 A CC (40-63 mµ). Radial chromatography was performed on 1-, 2-, or 4-mm plates of silica gel, depending on the amount of product. Medium-pressure chromatography (MPLC) was performed using silica gel 60 A CC (6-35 mµ). Band separation was monitored by UV. TLC plates were prepared by using Kieselgel 60 PF254. Solvents for chromatography were distilled at atmospheric pressure prior to use. Reaction solvents were purified and dried by using standard procedures.28 General Procedure for the Synthesis of Acyclonucleosides from 2,5-Dihydrofuran Derivatives. The 2,5-dihydrofuran derivative (1 mmol) in anhydrous chloroform (1 mL) was added to a solution of the silylated base (3 mmol) in anhydrous chloroform (2 mL). Then iodotrimethylsilane (1.3 mmol) was added and the reaction mixture was heated to reflux. The reaction mixture was then allowed to cool at room temperature and was poured into an aqueous solution of sodium bicarbonate. The aqueous layer was extracted with ethyl acetate, and the combination of extracts was washed with an aqueous solution of sodium thiosulfate (10%) and dried over MgSO4 and the solvent was evaporated under vacuum. The residue was purified by chromatography or by crystallization to obtain the acyclonucleoside. 1-[(2′Z)-2′-Buten-4′-acetoxy-1′-yl]thymine (12). Starting from 2,5-dihydrofuran (9, 100 µL, 1.32 mmol) and bis(trimethylsilyl)thymine (3.96 mmol), the general procedure of acyclonucleoside synthesis was applied maintaining the reaction at reflux for 10 min, to obtain an inseparable mixture of 10 and the E isomer (ratio Z/E ) 23:1). This mixture was then dissolved in anhydrous pyridine (1 mL) and treated with an excess of acetic anhydride (4 mmol). When the reaction was finished the mixture was poured into ice/water and was extracted with dichloromethane. The organic extracts were dried, evaporated under vacuum, and purified by MPLC (hexane to hexane/ethyl acetate 1:3) to obtain 241 mg (77%) of acetylated products. Crystallization of the mixture (ethyl acetate) provided compound 12 as colorless crystals (212 mg, 68%). Mp 113-115 °C. 1H NMR (CDCl3) δ 9.04 (s, 1H), 7.12 (q, 1H, J ) 1.2 Hz), 5.80 (dtt, 1H, J ) 10.8, 7.2, 1.2), 5.65 (dtt, 1H, J ) 10.8, 7.2 Hz, 1.2 Hz), 4.72 (dd, 2H, J ) 7.2, 1.6 Hz), 4.47 (dd, 2H, J ) 7.2, 1.2 Hz), 2.09 (s, 3H), 1.92 (d, 3H, J ) 1.2 Hz). 13C NMR (CDCl3) δ 170.9, 164.1, 150.8, 139.8, 128.5, 127.9, 111.1, 59.4, 44.3, 20.9, 12.3. Anal. (28) Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory Chemicals, 3rd ed.; Pergamon Press: Oxford, UK, 1989.

1174 J. Org. Chem., Vol. 68, No. 3, 2003

Calcd for C11H13N2O4: C, 55.46; H, 5.88; N, 11.77. Found: C, 55.56; H, 6.02; N, 11.83. 9-[(2′Z)-2′-Buten-4′-hydroxy-1′-yl]- N6-benzoyladenine (14). Starting from 2,5-dihydrofuran (9, 50 µL, 0.66 mmol) and (9) bis(trimethylsilyl)adenine (1.98 mmol), the general procedure for synthesizing acyclonucleosides was applied. The reaction was maintained for 30 min to obtain compound 14 as a mixture (ratio Z/E ) 5:1). Crystallization of the mixture (methanol) provided 110 mg (54%) of compound 14 as colorless crystals. Mp 174176 °C. 1H NMR (CD3OD) δ 8.57 (s, 1H), 8.27 (d, 2H), 8.24 (s, 1H), 7.54-7.42 (m, 3H), 5.85 (dtt, 1H, J ) 11.2, 6.0, 1.6), 5.79 (dtt, 1H, J ) 11.2, 6.4, 1.2), 5.35 (dd, 2H, J ) 6.0, 1.2), 5.21 (dd, 2H, J ) 6.4, 1.6). 13C NMR (CD3OD) δ 150.4, 148.9, 138.3, 134.6, 133.1, 130.9, 129.1, 126.4, 58.9, 48.2 (quaternary carbons not included, except carbonyl). Anal. Calcd for C16H15N5O2: C, 62.14; H, 4.86; N, 22.65. Found: C, 62.29; H, 5.00; N, 22.71. 9-[(2′Z)-2′-Buten-4′-hydroxy-1′-yl]-adenine (15).9 Compound 14 (123 mg, 0.40 mmol) was dissolved in PrNH2 (10 M in MeOH, 2.5 mL) and heated to reflux for 24 h. After evaporation the residue was purified by chromatography in a short column eluting with CH2Cl2/methanol 9:1 to give compound 15 as a syrup (56 mg, 69% yield). 1H NMR (DMSO-d6) δ 8.12 (s, 1H), 8.08 (s, 1H), 7.75 (br s, 2H), 5.65-5.52 (m, 2H), 4.15-4.05 (m, 2H). 13C NMR (DMSO-d6) δ 152.0, 139.0, 131.7, 127.2, 57.0, 37.2. (quaternary carbons not included). Anal. Calcd for C9H11N5O: C, 52.68; H, 5.36; N, 34.15. Found: C, 52.51; H, 5.28; N, 34.02. (3S,5R)-3-Phenylselenenyl-5-(tert-butyldiphenyl)silyloxymethyl-tetrahydrofuran (18a) and (3R,5R)-3-Phenylselenenyl-5-(tert-butyldiphenyl)silyloxymethyl-tetrahydrofuran (18b). Compound 17 (510 mg, 1.50 mmol) was dissolved in dichloromethane (23 mL) and then camphorsulfonic acid (104 mg, 0.45 mmol) and N-phenylselenophthalimide (544 mg, 1.80 mmol) were added. The resulting reaction mixture was heated to reflux for 12 h and was then left to cool at room temperature and filtered over a silica gel pad and the solvent evaporated under vacuum. The residue was purified by MPLC using linear gradient (hexane to hexane/ethyl acetate 5/1), to afford compounds 18a + 18b as a diastereoemeric mixture (ratio 25:75) (624 mg, 84%). Both compounds were separated by radial chromatography (hexane/ethyl acetate 10:1). 18a (higher Rf): [R]25D -6.6 (c 1.70. CHCl3). 1H NMR (CDCl3) δ 7.8-7.0 (m, 15H), 4.25-4.15 (m, 2H), 4.90-3.74 (m, 2H), 3.71 (dd, 1H, J ) 10.8, 4.5), 3.63 (dd, 1H, J ) 10.8, 4.2), 2.35 (ddd, 1H, J ) 13.2, 6.9, 6.0), 2.02 (ddd, 1 H, J ) 13.2, 7.5, 5.8), 1.04 (s, 9H). 13C NMR (CDCl3) δ: 135.7, 135.6, 134.2, 133.5, 129.7, 129.3, 129.2, 127.7, 127.6, 79.0, 74.4, 65.9, 39.3, 35.1, 26.7, 19.1. Anal. Calcd for C27H32O2SeSi: C, 65.44; H, 6.51. Found: C, 65.53; H, 6.65. 18b: [R]25D +19.3 (c 0.914. CHCl3). 1H NMR (CDCl3) δ 7.87.2 (m, 15H), 4.12 (dd, 1H, J ) 8.4, 6.6), 4.15-4.05 (m, 1H), 3.80 (td, 1H, J ) 8.4, 8.4, 1.5), 3.8-3.6 (m, 3H), 2.40 (dt, 1H, J ) 12.9, 7.0), 1.88 (dtd, 1H, J ) 12.9, 8.1, 1.5), 1.06 (s, 9H). 13C NMR (CDCl3) δ 135.7, 134.9, 134.2, 133.5, 129.7, 129.2, 127.7, 127.7, 127.6, 127.4, 79.6, 74.1, 65.9, 38.5, 35.1, 26.7, 19.1. Anal. Calcd for C27H32O2SeSi: C, 65.44; H, 6.51. Found: C, 65.60; H, 6.51. (5R)-5-(tert-Butyldiphenyl)silyloxymethyl-2,5-dihydrofuran (19). A mixture of compounds 18a + 18b (624 mg, 1.26 mmol) was dissolved in THF (8 mL) and cooled in an ice bath. Then pyridine (8 drops) and 10% H2O2 (2.4 mL, 7.56 mmol) were added. The reaction was stirred for 1 h and was then quenched by adding water. The reaction mixture was extracted with dichloromethane, and the organic phase was dried with magnesium sulfate and evaporated under vacuum. The residue obtained was purified by flash chromatography eluting with hexane/ethyl acetate 5:1, to obtain compound 19 as a white solid (391 mg, 92%). Mp 39-42 °C. [R]25D +69.3 (c 0.878. CHCl3). 1H NMR (CDCl3) δ 7.8-7.3 (m, 10H), 5.95 (ddd, 1H, J ) 6.3, 3.6, 1.8), 5.82 (ddt, 1H, J ) 6.3, 2.5, 1.5), 4.91 (dddt, 1H, J ) 4.8, 4.8, 3.6, 1.8, 1.5), 4.69 (ddd, 1H, J ) 12.8, 2.5, 1.8), 4.63 (ddd, 1H, J ) 12.8, 2.5, 1.8), 3.72 (dd, 1H, J ) 10.5, 4.8), 3.68 (dd, 1H, J ) 10.5, 4.8), 1.05 (s, 9H). 13C NMR (CDCl3) δ 135.7, 135.6, 133.7, 133.6, 129.6 (2 C), 127.8, 127.6 (2 C), 127.4, 86.6, 75.6,

66.5, 26.6, 19.1. Anal. Calcd for C21H26O2Si: C, 74.51; H, 7.74. Found: C, 74.21; H, 7.84. 1-[(4′R)-5′-O-tert-Butyldiphenylsilyl-2′-penten-4′,5′-diol1′-yl]thymine (20). Starting from compound 19 (110 mg, 0.32 mmol) and bis(trimethylsilyl)thymine (0.96 mmol), the general procedure of acyclonucleoside synthesis was applied maintaining the reaction at reflux for 12 h. The reaction crude was purified by radial chromatography (hexane/ethyl acetate 1:3) to obtain compound 20 as a foam (139 mg, 92%). [R]25D -40.4 (c 1.251. CHCl3). 1H NMR (CDCl3) δ 9.99 (s, 1H), 7.7-7.3 (m, 10H), 7.01 (s, 1H), 5.66 (dd, 1H, J ) 11.0, 7.4), 5.53 (m, 1H), 4.64 (q, 1H, J ) 6.3, 6.3, 6.3), 4.39 (dd, 1H, J ) 15.2, 8.4), 4.31 (ddd, 1H, J ) 15.2, 6.0, 1.2), 3.67 (dd, 1H, J ) 10.4, 6.8), 3.64 (dd, 1H, J ) 10.4, 5.2), 3.37 (br s, 1H), 1.87 (s, 3H), 1.08 (s, 9H). 13C NMR (CDCl3) δ 164.4, 151.2, 139.8, 135.5, 135.4, 133.7, 132.9, 132.8, 129.9, 129.8, 127.7, 126.1, 111.0, 68.3, 67.2, 44.9, 26.7, 19.1, 12.2. Anal. Calcd for C26H32N2O4Si: C, 67.21; H, 6.94; N, 6.03. Found: C, 67.15; H, 6.89; N, 5.98. 1-[(4′R)-2′-Penten-4′,5′-diol-1′-yl]thymine (21). A solution of compound 20 (120 mg, 0.26 mmol) in 2 mL of dry THF was treated with tetrabutylammonium fluoride (1 M solution in THF, 0.30 mmol) at 0 °C and under argon atmosphere. The reaction was monitored by TLC in ethyl ether/petroleum chloroform/ methanol 9:1. After 2 h the reaction mixture was left to warm to room temperature, poured into a water/ice mixture, and extracted with ether. The combination of extracts was concentrated and chromatographed in a short column eluting with CH2Cl2/methanol 9:1 to obtain compound 21 as an oil (56 mg, 97%). [R]25D -19.81 (c 1.060. CH3OH). 1H NMR (CD3OD) δ 7.27 (s, 1H), 5.57 (dd, 1H, J ) 10.8, 8.0), 5.47 (m, 1H), 4.46 (q, 1H, J ) 7.2, 7.2, 7.2), 4.40 (dd, 1H, J ) 15.2, 7.2), 4.35 (dd, 1H, J ) 15.2, 6.4), 3.48 (dd, 1H, J ) 11.2, 6.8), 3.41 (dd, 1H, J ) 11.2, 5.2),

1.79 (s, 3H). 13C NMR (CDCl3) δ 164.6, 150.8, 140.3, 133.4, 125.4, 109.9, 67.4, 64.9, 44.3, 11.1. Anal. Calcd for C10H14N2O4: C, 53.09; H, 6.19; N, 12.39. Found: C, 52.89; H, 6.08; N, 12.23. 9-[(4′R)-(5′-O-tert-Butyldiphenylsilyl-2′-penten-4′,5′-diol1′-yl]-N6-benzoyladenine (22). Starting from compound 19 (139 mg, 0.41 mmol) and bis(trimethylsilyl)-6N-benzoyladenine (1.23 mmol), the general procedure of acyclonucleosides synthesis was applied. The reaction was maintained for 12 h and the reaction crude was purified by MPLC using linear gradient (hexane to hexane/ethyl acetate 1:2) to obtain compound 22 as a foam (168 mg, 71%). [R]25D -12.03 (c 0.910. CHCl3). 1H NMR (CDCl3) δ 8.4 (s, 1H), 8.2 (d, 2H), 8.1 (s, 1H), 7.7-7.6 (m, 4H), 7.5-7.1 (m, 9H), 5.86 (dddd, 1H, J ) 11.2, 7.2, 6.4, 1.6), 5.66 (ddt, 1H, J ) 11.2, 11.2, 6.4, 1.2), 5.23 (ddd, 1H, J ) 14.8, 6.4, 1.6), 5.08 (ddd, 1H, J ) 14.8, 7.2, 1.6), 4.70 (m, 1H), 3.70 (dd, 1H, J ) 10.4, 4.0), 3.64 (dd, 1H, J ) 10.4, 8.), 1.08 (s, 9H). 13C NMR (CDCl3) δ 175.4, 146.6, 141.4, 132.1, 137.5, 135.6, 135.5, 131.9, 130.1, 130.0, 129.8, 128.1, 127.9, 127.1, 69.3, 67.4, 47.3, 26.8, 19.2. Anal. Calcd for C33H35N5O3Si: C, 68.63; H, 6.07; N, 12.13. Found: C, 68.92; H, 6.17; N, 11.98.

Acknowledgment. Financial support by DGESIC PB98-1510 (Ministerio de Educacio´n y Cultura, Spain) is acknowledged. F.B. thanks CIRIT (Generalitat de Catalunya) for a grant. Technical assistance by the Servei de Recursos Cientı´fics (URV) is acknowledged. We thank Prof. Frank E. McDonald (Emory University) for suggestions and for the careful reading of the manuscript. JO010948R

J. Org. Chem, Vol. 68, No. 3, 2003 1175